Myocarditis is an inflammatory pathology of the myocardium, driven by both infectious and non-infectious agents, that often precedes acute heart failure, ventricular arrhythmias, and dilated cardiomyopathies. Thus, understanding the mechanisms that regulate its onset and resolution is crucial for the prevention and treatment of myocardial disease. MicroRNAs are short non-coding RNAs that fine-tune inflammatory responses by post- transcriptionally regulating immune genes. Of these, miR-208b and miR-499-5p, members of a family of microRNAs specific to skeletal muscle and cardiac tissue (myomiRs) are aberrantly expressed in patients with acute myocardial inflammation and predict disease severity. However, the biological significance of these observations is poorly understood. We have previously shown that miR-208b and miR-499-5p, are aberrantly induced by viral infection and associated antiviral cytokines in hepatocytes, where they silence both type I and type III interferon (IFN) responses resulting in diminished viral clearance. In this study, we are proposing that cardiomyocytes have evolved a similar mechanism to block interferon-mediated inflammation, which cardiotropic viruses utilize to avoid immune detection and elimination. We propose that miR-208b and miR- 499-5p expression in the heart is elevated by proinflammatory injury and results in the loss of inflammatory control and the premature resolution of crucial antiviral responses that render cardiomyocytes susceptible to cellular death and could promote cardiac tissue damage. We propose to identify the distinct damage- associated stimuli that regulate myomiR expression and how these coordinate inflammatory responses. We will use unbiased approaches to identify the key molecular targets regulated by myomiRs. We will test if myomiRs antagonize antiviral responses that leads to persistence of viral infections associated with myocardial disease. Overall, our integrative approach will build a comprehensive gene regulatory network that encompasses the complex interactions between microRNAs, host immune responses, tissue repair and viral clearance in cardiac disease, from which we can discover novel molecular targets for therapeutic intervention.